Is ANO5 p.Phe686Val (c.2056T>G) pathogenic?

ANO5 p.Phe686Val (c.2056T>G) is classified Uncertain significance in ANO5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-08). AlphaMissense: likely pathogenic (0.9822); Absent from gnomAD v4.1; Associated with gnathodiaphyseal dysplasia.

What condition is associated with ANO5 p.Phe686Val (c.2056T>G)?

ANO5 p.Phe686Val (c.2056T>G) is associated with gnathodiaphyseal dysplasia, autosomal recessive limb-girdle muscular dystrophy type 2L (ClinVar).

How common is ANO5 p.Phe686Val (c.2056T>G) in the general population?

ANO5 p.Phe686Val (c.2056T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ANO5 p.Phe686Val (c.2056T>G)?

AlphaMissense predicts likely pathogenic (score 0.9822) — an in-silico prediction, not a clinical call.

ANO5 p.Phe686Val

c.2056T>G · rs1554934237 · VCV536725

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9822 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

gnathodiaphyseal dysplasia

Computational evidence

Protein change
AlphaMissense	0.9822	likely pathogenic · top 7% in ANO5
REVEL	0.944	strongly pathogenic-leaning
SaProt	LLR -13.08	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.41 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 86 kb · p 0.66 · regional, not allelic
Overall
CADD	28.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ANO5
Protein: p.Phe686Val
Coding: c.2056T>G
MANE Select: NM_213599
dbSNP: rs1554934237
Type: single nucleotide variant
Location: chr11:22272810 (GRCh38)
Gene constraint: LOEUF 1.034 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.22
Residue 686: a UniProt-annotated variant site (in lgmdr12); a UniProt-annotated variant site (in lgmdr12; uncertain significance)

Full ANO5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

gnathodiaphyseal dysplasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive limb-girdle muscular dystrophy type 2L

Similar variants

ANO5 c.1898+1G>A Pathogenic ★★★ same condition
ANO5 c.41-1G>A Pathogenic ★★★ same condition
ANO5 p.Ala432Gly Pathogenic ★★★ ⚠ same condition
ANO5 p.Arg484Cys Likely pathogenic ★★★ same condition
ANO5 p.Arg50Ter Pathogenic ★★★ same condition
ANO5 p.Arg58Trp Pathogenic ★★★ ⚠ same condition
ANO5 p.Arg758Cys Pathogenic ★★★ same condition
ANO5 p.Asp81Gly Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ano5-p-phe686val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown